The reduction of organic substrates, e.g. an ester, acid or ketone to an alcohol and an amide, nitrile or imide to an amine is a key transformation for the development of pharmaceutical drugs such as antibacterials, HIV inhibitors and ocular hypertension drugs. These transformations are difficult to complete selectively in the presence of other sensitive reducible functional groups. The introduction of new methods for the reduction of these organic substrates, especially of esters and amides is highly desirable.
Amine borane complexes are very stable borane sources. The borane complexes of amines are easily used on a large scale but generally less reactive than borane complexes of ethers or sulfides. Some amine boranes are even stable to aqueous solution over extended periods of time. Their applications in organic synthesis have been limited due to their low reactivity toward functional groups. In contrast to other more reactive borane complexes such as borane tetrahydrofuran (BTHF) or dimethylsulfide borane (DMSB), acidic conditions or elevated temperatures are normally required in reductions with amine boranes. Pyridine borane and trimethylamine borane are often insufficiently reactive to accomplish the amide reduction. Borane derivatives of dialkylanilines and sterically hindered amines are significantly more reactive than other amine boranes but still require prolonged heating at elevated temperatures to drive the amide reduction to completion, see Brown, H. C.; Kanth, J. V. B.; Zaidlewicz, M. J. Org. Chem. 1998, 63(15), 5154-5163. Salunkhe, A. M.; Burkhardt, E. R. Tetrahedron Letters 1997, 38(9), 1519; Brown, H. C.; Kanth, J. V. B.; Dalvi, P. V.; Zaidlewicz, M. J. Org. Chem. 1999, 64(17), 6263-6274. Kanth, J. V. B. Aldrichimica Acta 2002, 35, 57. Burkhardt and Salunkhe reported that N,N-diethylaniline borane (DEANB) efficiently reduced a variety of functional groups such as aldehydes, ketones, carboxylic acids, esters and tertiary amides at elevated temperature. Esters and hindered ketones required extensive reaction time at reflux in THF to drive the reaction to completion. These examples demonstrated lower reactivity of DEANB versus BTHF and DMSB, see Bonnat, M.; Hercouet, A.; Le Corre, M. Synthetic Communications 1991, 21(15-16), 1579-82. However, due to the thermal ether cleavage of BTHF and the stench of DMSB, high volume use of these borane reagents for ester and amide reductions is limited.
The reduction of the ester functionality with borane complexes requires harsh conditions, generally requiring refluxing conditions to effectively push the reduction to completion. Several examples exist using BTHF or DMSB for this purpose, see Sessler, J. L. et al. Inorg. Chem. 1993, 32, 3175 and Brown, H. C.; Choi, Y. M.; Narasimhan, S. J. Org. Chem. 1982, 47(16), 3153-63. When DMSB is used, the dimethyl sulfide is usually distilled from the refluxing solution to drive the reduction to completion. For example, selective reduction one ester of L-maleic acid dimethylester using DMSB successfully produced 3(S)-4-dihydroxybutyric acid methyl ester. Amine boranes generally do not reduce the ester functionality. However, due to the thermal ether cleavage of BTHF and the stench of DMSB, high volume use of these borane reagents is limited. Clearly, new methods must be developed for ester reductions.
The reduction of tertiary amides is generally faster than secondary or primary amides. To reduce the amide to amine, five hydride equivalents are required. Two of the hydrides are used to reduce the amide to amine and the other three hydrides are utilized to form the amine borane complex. Alternatively, BF3 (one equivalent relative to substrate) can be added to complex the amine and lower the amount of borane required for the reduction to ⅔ of a mole “BH3” per mole of substrate, see Brown, H. C.; Narasimhan, S.; Choi, Y. M. Synthesis 1981, (12), 996-7.
As discussed above, one equivalent of BF3 has been used to decrease the amount of borane used in amide reductions with BTHF. But the concept of adding boron trifluoride in a catalytic amount has not been tested as a Lewis acid accelerator for the amide reduction. Furthermore, the use of BF3 or other Lewis acids to activate esters toward reduction has not been addressed in the current literature.